The nervous system is composed of an enormous number of neurons, precisely connected into an intricate network, subserving the anatomical basis for all behaviors. Abnormal development of neural circuitry may cause various neurological and mental disorders. The long-term objective is to understand the molecular and cellular mechanisms of axon guidance during the wiring of the functional nervous system. The discovery of the proposed research will also provide clues for axonal regeneration studies following injury in the adult central nervous system. The mechanisms of axon wiring along the anterior-posterior axis of the central nervous system (the connections between the brain and the spinal cord) have remained a long-standing mystery. Wnt-Frizzled signaling was recently shown required for the A-P guidance of spinal cord commissural axons. However, the growth cone signaling mechanisms that mediate responsiveness to Wnt proteins are unknown. Three pathways are currently known to mediate Wnt actions: the canonical beta-catenin pathway, the planar cell polarity (PCP) pathway and the Ca++/PKC pathway. This grant proposes to test the role of the PCP pathway (Aim1), the PKC pathway (Aim2) and the canonical pathway and potentially novel pathways (Aim3) in axon guidance using commissural axons as a model system. This grant will also explore the possibility that more than one pathway might be involved in different aspects of guidance events, advancing the understanding cellular mechanisms of axon guidance. The finding that Wnt proteins can act as axon guidance cues provides more opportunity for understanding brain wiring. The proposed studies will provide foundation for future studies on the mechanisms how sensory pathways are guided to project anteriorly (from the spinal cord to the brain) and motor pathways to project posteriorly (from the brain to the spinal cord) and may also address the biological role of Wnt gradients in patterning neuronal networks in the central nervous system.